The importance of oocyte-granulosa cell communication throughout oogenesis is well accepted. Members of the TGF-beta superfamily are important mediators of oocyte-granulosa cell communication, but the direct effect of these ligands on the oocyte is unclear. TGF-beta ligands activate SMAD proteins in target cells through phosphorylation. Activated SMADs (SMAD2/3 and 1/5/9) bind SMAD4 and translocate to the nucleus where they regulate nuclear functions. Based on preliminary analysis of mutant animals were the Smad4 gene is non-functional in oocytes, the present project tests the hypotheses that (1) Smad4 deletion in oocytes causes increased follicular development and (2) Smad4 mutant oocytes are more bioactive than control oocytes. Together, results from these two aims will provide valuable insight into mechanisms that affect oocyte development and may allow for development of interventions to improve oocyte quality and ovarian function. PUBLIC HEALTH RELEVANCE: The proposed research activities will increase our understanding of ovarian function, follicular and oocyte development. This knowledge will improve our ability to treat problems associated with defects in female reproduction, including infertility, premature ovarian failure and irregular menstrual cycles.